As a member of B7 family, V-domain Ig suppressor of T cell activation (VISTA), also referred to as PD-1H, DD1α, c10orf54, Gi24, Dies1 and B7-H5, plays an important role in the regulation of T-cell responses (Nowak E. C. et al., (2017) Immunol Rev. 276(1): 66-79). It is a type I transmembrane protein whose extracellular domain bears homology to PD-L1, and expressed on hematopoietic cells, antigen-presenting cells, T cells and etc. (Lines J. L. et al., (2014) Microenvironment and Immunology. 74(7): 1924-32).
VISTAs, when expressed on antigen-presenting cells, bind as coinhibitory ligands to receptors on T cell surfaces to suppresse T cell responses. VISTAs were also expressed on CD4+ T cells as coinhibitory receptors (Flies D. B. et al., (2014) J Clin Invest. 124(5):1966-1975). CD4+ and CD8+ T cells stimulated with anti-CD3 in the presence of VISTA-Ig fusion protein proliferated less and produced reduced amounts of IFNγ and IL-2 (Lines J. L. et al., (2014) supra; Wang L. et al., (2011) J Exp Med. 208(3):577-592). Myeloid-derived suppressor cells (MDSC) isolated from mice infected with LP-BM5 retrovirus inhibited B cell proliferation in a VISTA dependent manner (Green K. A. et al., (2015) J Virol. 89(18): 9693-9698). Further, VISTA overexpression on MCA105 fibrosarcoma line, which naturally produced no such proteins, significantly increased tumor growth (Wang L. et al., (2011) supra).
VISTA is highly expressed within the tumor microenvironment (TME) on, e.g., monocytic myeloid derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs), and anti-VISTA monotherapy reshaped the suppressive nature of the TME by reducing the number of MDSCs and tumor specific Tregs (Lines, J. L. et al., (2014) Cancer Res. 74(7):1924-1932). The monotherapy with a blocking anti-VISTA monoclonal antibody significantly reduced tumor growth in many solid tumor models, including B16/OVA melanoma, B16/BL6 melanoma, MB49 bladder carcinoma, and PTEN/BRAF inducible melanoma, regardless of the immunogenic status or origin (Mercier I. L. et al., (2014) Cancer Res. 74(7):1933-1944). These promising results from animal tumor studies led to phase I/II anti-VISTA monotherapy clinical trials with anti-VISTA antibodies JNJ-61610588 and JNJ-63723283 (both from Janssen) in patients with advanced solid tumors, e.g., non-small cell lung cancer (NCT02671955: A study of safety, pharmacokinetics, pharmacodynamics of JNJ-61610588 in participants with advanced cancer; Calvo E. et al., (2018) Clinical Oncology 36(5-suppl):58). In another ongoing clinical trial, patients with advanced tumors and lymphomas were administered with a small molecule CA-170 (Curis) antagonizing VISTA, PD-L1 and PD-L2 pathways (NCT02812875: A study of CA-170 (oral PD-L1, PD-L2 and VISTA checkpoint antagonist) in patients with advanced tumors and lymphomas). Combination therapies of anti-VISTA antibody with drugs targeting CTLA-4, PD-1 or other negative checkpoint regulators were also extensively discussed and studied (Deng J. et al., (2016) J Immunother Cancer. 4:86; Kondo Y. et al., (2015) J Immunol. 194(1_suppl): 69.32; Kondo Y. et al., (2016) Oral Oncol. 57: 54-60).
There remains a need for more anti-VISTA antibodies with improved pharmaceutical characteristics.